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Objective: Abnormal glutamatergic neurotransmission is implicated in the pathophysiology of autism spectrum disorder (ASD). In this study, the safety, tolerability, and efficacy of the glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist memantine (once-daily extended-release [ER]) were investigated in children with autism in a randomized, placebo-controlled, 12 week trial and a 48 week open-label extension., Methods: A total of 121 children 6-12 years of age with Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR)-defined autistic disorder were randomized (1:1) to placebo or memantine ER for 12 weeks; 104 children entered the subsequent extension trial. Maximum memantine doses were determined by body weight and ranged from 3 to 15 mg/day., Results: There was one serious adverse event (SAE) (affective disorder, with memantine) in the 12 week study and one SAE (lobar pneumonia) in the 48 week extension; both were deemed unrelated to treatment. Other AEs were considered mild or moderate and most were deemed not related to treatment. No clinically significant changes occurred in clinical laboratory values, vital signs, or electrocardiogram (ECG). There was no significant between-group difference on the primary efficacy outcome of caregiver/parent ratings on the Social Responsiveness Scale (SRS), although an improvement over baseline at Week 12 was observed in both groups. A trend for improvement at the end of the 48 week extension was observed. No improvements in the active group were observed on any of the secondary end-points, with one communication measure showing significant worsening with memantine compared with placebo (p = 0.02) after 12 weeks., Conclusions: This trial did not demonstrate clinical efficacy of memantine ER in autism; however, the tolerability and safety data were reassuring. Our results could inform future trial design in this population and may facilitate the investigation of memantine ER for other clinical applications.

Introduction: Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors., Methods: In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations., Results: A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of ≥5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %)., Conclusion: Extended-release memantine was efficacious, safe, and well tolerated in this population.

Background: This study was designed to assess changes in brain volume and cognitive abilities in memantine-treated patients with Alzheimer's disease (AD) by using an exploratory, single-arm, delayed-start design., Methods: Cholinesterase inhibitor-treated patients with AD (N = 47; Mini-Mental State Examination score range: 15-23) were enrolled in an observational lead-in period (weeks: 1-24), followed by an open-label period of add-on memantine treatment (weeks: 25-48). The patients underwent magnetic resonance imaging at weeks 0 (baseline), 24 (immediately before memantine initiation), and 48 (endpoint), and a battery of neuropsychological tests at weeks 0, 24, 28, 36, and 48. The primary outcome measure was the annualized rate of change (%) in total brain volume (TBV) between the two study periods. Data were analyzed using paired t-tests., Results: There were no statistically significant differences in the rates of change in TBV, ventricular volume, or left hippocampal volume between the study periods; however, the memantine treatment period was associated with a significantly slower right hippocampal atrophy (-5.5% ± 12.0% vs -10.8% ± 7.2%; P = .038). Memantine treatment was also associated with superior performances on the Boston Naming Test (P = .034) and the Trail Making Test, Part B (P = .001), but also with a higher number of errors (i.e., repetitions and intrusions) on the California Verbal Learning Test. Memantine was found to be safe and well tolerated., Conclusions: In this study, no difference in the rates of TBV change between the two periods was observed; however, memantine treatment was found to be associated with slowing of right hippocampal atrophy, and with improvement on one test of executive functioning as well as a test of confrontation naming ability. Trials using structural magnetic resonance imaging and a delayed-start design may be a feasible option for the assessment of treatments for AD., (Copyright © 2011 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Taurolidine is an experimental antibacterial and antiendotoxic compound whose clinical utility as an antitumor agent is being investigated in human clinical trials. Taurolidine in aqueous solution exists in equilibrium with taurultam. Taurultam is subsequently transformed to taurinamide. The pharmacokinetic profiles of these metabolites are not well established. In this study, 18 healthy volunteers were administered 5.0 g of taurolidine in 250 mL of 5% polyvinylpyrrolidone in water over 2, 1, or 0.5 hours by intravenous infusion in a parallel-group design. All subjects noted discomfort at the infusion site, although there were no serious adverse events. t(max) generally occurred at the end of infusion for taurinamide, whereas that of taurultam was reached before completion of infusion. The taurolidine metabolite taurultam demonstrated a shorter half-life and lower systemic exposure than taurinamide. Shortening of infusion duration increased the C(max) and AUC of taurultam. Changes in infusion rate did not substantially change the pharmacokinetic parameters of taurinamide.

Purpose: This open-label study investigated the pharmacokinetic interaction of phenytoin (PHT) and felbamate (FBM)., Methods: Ten subjects with epilepsy receiving PHT monotherapy were administered increasing doses of FBM (1,200, 1,800, 2,400-3,600 mg/day) at 2-week intervals. PHT doses were reduced by 20% on an individual basis when evidence of clinically significant intolerance was present. With intolerance, the PHT dose was reduced before the next incremental FBM dose. Blood samples were analyzed for FBM, PHT, and PHT metabolite 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH)., Results: Total PHT plasma concentrations increased with coadministered FBM. PHT Cmax increased from 15.9 microg/ml at baseline to 20.9 microg/ml after 1,200 mg/day FBM and to 26.8 microg/ml after 1,800 mg/day FBM. Four subjects required a 20% PHT dose reduction after 1,800 mg/day FBM and six after the administration of 2,400 mg/day FBM. All subjects required further 20% PHT reductions before 3,600 mg/day FBM. FBM Cmax and AUCT were reduced, and apparent clearance increased compared with data from FBM monotherapy., Conclusions: With the initiation of FBM therapy in subjects receiving PHT, the PHT dosage should be reduced by 20%. Further PHT dose reductions are likely to be necessary if the FBM dose is increased. The requirements for reductions in dose might be predicted by clinical signs of PHT intolerance.

Purpose: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine., Methods: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population., Results: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured., Conclusions: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.

Felbamate (FBM) is a novel antiepileptic drug that was approved in 1993 for treatment of several forms of epilepsy. After its introduction, toxic reactions (aplastic anemia and hepatotoxicity) associated with its use were reported. It is unknown whether FBM or one of its metabolites is responsible for these idiosyncratic adverse reactions. Although the metabolism of FBM has not been fully characterized, three primary metabolites of FBM have been identified, i.e. 2-hydroxy, p-hydroxy, and monocarbamate metabolites. In addition, the monocarbamate metabolite leads to a carboxylic acid, which is the major metabolite of FBM in humans. Formation of the hydroxylated products of FBM involves cytochrome P450 enzymes, but the enzymes involved in the formation and further metabolism of the monocarbamate have not yet been elucidated. Recently, mercapturate metabolites of FBM have been identified in human urine, and a metabolic scheme involving reactive aldehyde metabolite formation from the monocarbamate metabolite has been proposed. The present study confirmed the formation of the proposed metabolites using human liver tissue in vitro. The aldehyde intermediates were trapped as oxime derivatives, and the cyclic equilibrium product (proposed as a storage and transport form for the aldehydes) was monitored directly by HPLC or GC/MS. Formation of putative toxic aldehyde intermediates and the major carboxylic acid metabolite of FBM was differentially effected with the cofactors NADP+ and NAD+. It is possible that the cofactors may influence the relative metabolism via activation and inactivation pathways.

Effects of erythromycin on hepatic CYP450 3A4 isozymes can profoundly influence the metabolism of many therapeutic agents. An open-label, randomized, two-period, crossover study was therefore conducted to evaluate the pharmacokinetics of felbamate before and after a concurrent 10-day regimen (333 mg three times daily) of erythromycin. Patients were receiving either 3,000 or 3,600 mg/day felbamate monotherapy for treatment of epilepsy. Mean dose-normalized values for maximum concentration (Cmax) and area under the concentration-time curve (AUC tau) of felbamate were not statistically different in patients taking felbamate as monotherapy than in patients after erythromycin coadministration. Estimates of time to Cmax (tmax), minimum concentration (Cmin), apparent clearance (Cl/kg), average concentration (Cav), and degree of fluctuation (DFss) were likewise unchanged. The incidence of mild and moderate adverse events increased during coadministration of the two drugs. Because patients with epilepsy can not be treated with erythromycin alone, it could not be determined whether the adverse events were attributable to erythromycin or to the combination of the two drugs. Steady-state pharmacokinetic parameters of felbamate were not influenced by erythromycin coadministration.

Azelastine, an antihistamine with additional pharmacologic properties, was evaluated for a possible influence on pharmacokinetic and electrocardiographic parameters due to its coadministration with CYP3A4 inhibitor ketoconazole (200 mg every 12 hrs). Twelve volunteers entered this three-period, open-label study. Electrocardiographic parameters (PR, QRS and QTc intervals and U-wave morphology) were monitored after 14 days of azelastine HCl (4.4 mg every 12 hrs), after 7 days of either azelastine/ketoconazole or azelastine/placebo, and after a 21-day washout period, which was then followed by a 7-day administration of ketoconazole alone. None of the treatments resulted in meaningful alterations of electrocardiographic variables. Pharmacokinetic parameters could not be estimated because ketoconazole metabolites interfered with azelastine assay procedures. In vitro tests with human liver microsomes were used to characterize azelastine's inhibition spectrum. Azelastine did not inhibit CYP3A4 activity but it did inhibit CYP2D6 and CYP2C19 activity with Ki values exceeding maximum plasma concentration by 120 to 800-fold. Therefore, in vitro tests and the absence of electrocardiographic effects suggests azelastine can be safely administered with CYP3A4 inhibitors.

This article provides an analysis of the degree of agreement between in vivo interaction studies performed in patients with epilepsy and healthy individuals, and in vitro studies which identified the cytochromes P450 (CYP) inhibited by felbamate and those involved in its metabolism. In vitro studies show that felbamate is a substrate for CYP3A4 and CYP2E1. Compounds which induce CYP3A4 (e.g. carbamazepine, phenytoin and phenobarbital) increase felbamate clearance. However, the CYP3A4 inhibitors gestodene, ethinyl estradiol and erythromycin have little or no effect on felbamate trough plasma concentrations, consistent with the fact that the pathway is relatively minor for felbamate under normal (non-induced) conditions. Felbamate has been shown in vitro to inhibit CYP2C19, which would account for its effect on phenytoin clearance, and it had been postulated that this could be the mechanism underlying the reduced clearance of phenobarbital by felbamate. Although not yet examined in vitro, felbamate appears to induce the activity of CYP3A4, which would account for it reducing plasma concentrations of carbamazepine or the progestin gestodene. Interactions involving felbamate and non-CYP450-mediated metabolic pathways have also been addressed in clinical studies. The reduction in valproic acid (valproate sodium) clearance by felbamate is through the inhibition of beta-oxidation. No clinically relevant pharmacokinetic interactions were noted between felbamate and lamotrigine, clonazepam, vigabatrin, nor the active monohydroxy metabolite of oxcarbazepine. Information on the mechanisms underlying felbamate's drug:drug interaction profile permits predictions to be made concerning the likelihood of interactions with other compounds.

Purpose: Felbamate (FBM) pharmacokinetic parameters, safety and tolerability in the dose range of 1,200-6,000 mg/day were assessed in two open-label studies with similar designs., Methods: In study A, newly diagnosed subjects with epilepsy receiving FBM monotherapy at a starting dose of 1,200 mg/day (400 mg/three times daily, t.i.d.) and increased 1,200 mg/day, if tolerated, at 14-day intervals to 3,600 mg/day were investigated. In study B, epilepsy subjects with prior FBM monotherapy exposure received ascending FBM doses in five consecutive 14-day periods with a starting dose of 3,600 mg/day (1,200 mg t.i.d.) FBM. In each successive period, if FBM was well tolerated, the dose was increased by 600 mg/day to a maximum of 6,000 mg/day (2,000 mg t.i.d.)., Results: The pharmacokinetic parameter estimates maximum observed concentration (Cmax), area under the concentration-time curve (AUCtau) Ctrough, and Cav showed a linear dependence to dose above the 1,200-6,000 mg/day FBM dose range (F-tests; p < 0.0001) with apparent clearance (Cl/kg) and Tmax (time to Cmax) independent of dose. When AUCtau, Cmax and Ctrough were adjusted for dose, there were no significant differences between the dosing periods., Conclusions: The data establish that plasma concentrations of FBM are linear with respect to dose to 6,000 mg/day. In addition, FBM was safely administered at these doses for periods as long as 14 days to epileptic subjects with prior exposure to FBM. FBM-naive subjects appeared to report more adverse experiences (generally of mild to moderate severity) than did subjects with prior FBM exposure.

The effects of age on felbamate apparent clearance were examined through a retrospective analysis of plasma concentration data from 700 pediatric and adult epileptic patients (age range, 2-74 years) enrolled in six clinical studies. Patients received felbamate as monotherapy or in combination with either the antiepileptic drugs (AEDs) carbamazepine (CBZ), phenytoin (PHT), or valproate (VPA). Data were analyzed using a nonlinear mixed-effects pharmacostatistical modeling technique (NONMEM). Factors in the model included age, body weight, and concomitant AEDs. Apparent clearance was highest in the very young and decreased during the early teenage years, with minimal changes observed beyond 13 years. Mean apparent clearance values were approximately 40% higher in children (2-12 years) compared with those in adults (13-65 years). This pattern and its magnitude were consistent whether felbamate was administered alone or coadministered with CBZ, PHT, or VPA. The increase in clearance is minimal compared with other AEDs including PHT, CBZ, and phenobarbital. Enzyme-inducing AEDs (CBZ and PHT) increased felbamate apparent clearance by 32-38% relative to monotherapy, whereas coadministration with VPA had a minimal effect on felbamate apparent clearance. Dose/concentration linearity was observed at all ages during mono- or polytherapy. These findings suggest that felbamate dosing should be relatively uncomplicated in children relative to that in adults.

The objective of this double-blind trial was to evaluate the corticosteroid-sparing effect of azelastine in patients with chronic bronchial asthma. A total of 193 subjects received either 6 mg of azelastine twice per day or placebo (in a 2:1 ratio) in combination with beclomethasone dipropionate (6 to 16 inhalations per day). The number of daily inhalations of the corticosteroid was reduced until maximum reduction or elimination was achieved. Patients then entered a 12-wk maintenance period, during which patients were maintained on their lowest possible dose of inhaled corticosteroid. Compared with placebo, the azelastine group had a statistically significantly greater overall median reduction in inhaled corticosteroids (4.9 puffs/day for azelastine versus 3.1 puffs/day for placebo; p < or = 0.010) during the maintenance period. The azelastine group also had a statistically significantly higher percentage of patients with reductions of > or = 50% and > or = 75% from the baseline level (53 and 31%, respectively, for azelastine versus 34 and 14%, respectively, for placebo; p < or = 0.028). The results demonstrated that azelastine, 6 mg twice per day, can reduce the need for inhaled corticosteroids in patients with chronic bronchial asthma and not lead to a deterioration in pulmonary function.

Introduction: Felbamate is a new antiepileptic drug approved for partial and secondarily generalized seizures., Design: Subjects with epilepsy (three men and seven women; age range, 20 to 39 years; weight range, 53 to 88 kg) who were previously stabilized with valproic acid, 9.5 to 31.7 mg/kg/day, received both 600 and 1200 mg felbamate twice a day in an open-label, randomized, crossover study., Results: Coadministration of 1200 or 2400 mg felbamate increased the mean valproic acid area under the curve (from 802.2 to 1025.4 and 1235.9 mg/hr/ml, respectively), peak concentrations (from 86.1 to 115.1 and 133.4 mg/ml, respectively), and average steady-state concentrations (from 66.9 to 85.5 and 103.0 mg/ml, respectively). No changes were observed in valproic acid time to peak concentration or protein binding. Average steady-state felbamate concentrations were 34.7 mg/ml for 600 mg administered twice daily and 61.2 mg/ml for 1200 mg administered twice daily., Conclusion: When felbamate is added to a regimen of valproic acid, valproic acid doses may require reduction because coadministration of felbamate decreased steady-state valproic acid clearance (28% and 54%, respectively; p < 0.01).

Azelastine is a novel, orally effective, long-acting, antiallergic agent. The ability of azelastine to influence calcium ionophore A23187-induced histamine release from rat peritoneal mast cells was investigated and compared with selected antiallergic drugs. The concentrations of drugs required to inhibit A23187 (0.2 microM)-stimulated histamine release by 50% (IC50S, microM) were as follows: azelastine 5; diphenhydramine 52; and ketotifen 200. Theophylline and sodium cromoglycate in a concentration range of 0.1-1000 microM failed to exert any significant inhibition of histamine release. The inhibitory effects of azelastine on A23187-stimulated histamine release were antagonized by high concentrations of exogenous Ca2+ ions. These data suggest that azelastine inhibits A23187-stimulated histamine release by interfering with the influx of Ca2+ into the mast cells.

A broad antiallergic compound called azelastine was studied pharmacodynamically in 34 subjects to correlate bronchodilator effect with blood levels of azelastine and desmethyl azelastine, its major metabolic product in man. Despite azelastine and desmethyl azelastine blood levels that were proportionate to the dosage range, the bronchodilator effect as measured by FEV1 and forced expiratory flow rate between 25% and 75% of FVC was proportionately greater with 4 mg of azelastine during the 8-hour study period than the anticipated bronchodilator response with the 8 and 16 mg doses. Azelastine, already proven effective in allergic rhinitis, has a bronchodilator effect at doses that do not produce intolerable side effects.

Azelastine is an orally effective inhibitor of mediator activity in allergic reactions and has also been demonstrated to have bronchodilator activity. In this randomized, double-blind, placebo-controlled, multicenter study, 150 patients, aged 12 to 60 years, with moderate to severe asthma, received a single oral dose of 2, 4, 8, 12, or 16 mg of azelastine or placebo. Theophylline was stopped 24 hours and other bronchodilators at least 8 hours before the study day. Patients were evaluated for 8 hours after dose by spirometry and were monitored for adverse effects. All doses of azelastine produced bronchodilation with 4 mg greater than 2 mg greater than placebo; higher doses did not increase magnitude or duration of effect. We conclude that azelastine produces significant bronchodilation of long duration. The optimal dose appears to be 4 mg for adolescent and adult patients with asthma.

Calcium plays a critical role in the formation and secretion of a wide variety of chemical mediators. Calcium slow-channel blockers, e.g. nifedipine and verapamil, have been shown to inhibit the synthesis of SRS (SRS-A, leukotrienes) in human and guinea pig lung tissue, thromboxane A2 formation in rat lung and platelet activating factor in human neutrophils. Verapamil and nifedipine also prevent the release of lysosomal enzymes from rabbit and human polymorphonuclear neutrophils. Calcium-channel blockers produce variable inhibitory effects on allergic and nonallergic histamine secretion. Ca++-entry blockers also inhibit the Ca++ uptake (influx) into mast cells. Many of these inhibitory effects of Ca++ antagonists are antagonized by an increased extracellular Ca++ ion concentration. The magnitude of the inhibitory influences of Ca++-channel blockers on allergic and nonallergic release of chemical mediators appears to depend on the cell source, species, nature and the concentration of the secretory stimuli as well as on the composition and pH of buffers and the concentration of Ca++-entry blockers used. The data summarized in this review suggest the existence of a functional heterogeneity of Ca++ channels in leukocytes, mast cells and basophils. Interference with the Ca++-dependent steps involved in the formation and/or release of chemical mediators appears to be the primary mode of action for Ca++-channel blockers in these cells. The differential effects of Ca++ antagonists on Ca++-dependent activation of phospholipase A2,5-lipoxygenase, and calmodulin (or other intracellular Ca++-binding proteins) in different cell types (mast cells, basophils, leukocytes, lung tissue, etc.) may explain the variation of their effectiveness in inhibiting the synthesis/release of chemical mediators and antagonizing bronchoconstriction in response to diverse stimuli. During the process of hypersensitization and in immediate hypersensitivity diseases, Ca++ homeostasis (uptake, mobilization, distribution, relocation, etc.) may be altered in leukocytes (mast cells, basophils) and lung tissues. The altered Ca++ homeostasis could be responsible for the induction of airway hyperreactivity in asthmatics and for hyperreleasability of chemical mediators from leukocytes, mast cells and other cell types.(ABSTRACT TRUNCATED AT 250 WORDS)

Flupirtine, a chemically unique, orally effective, non-narcotic, centrally acting analgesic was evaluated for efficacy and safety in five parallel, double-blind randomized clinical trials which included both placebo and active control comparisons. Flupirtine was given in oral doses of 100 to 300 mg, with a maximum daily dose of 600 mg to patients with pain resulting from episiotomy, surgical or dental procedures. Patients rated pain intensity, pain relief and adverse experiences at regular intervals up to 6 hours following medication. Assessments of efficacy included measures of the sum of pain intensity differences (SPID), total pain relief (TOPAR) and peak analgesia (PPID). More than 1300 patients have been evaluated at 26 study sites in the United States. More than 170 of them received flupirtine 100 mg, 250 received 200 mg and 50 received 300 mg. An additional 415 patients received positive control medications (paracetamol 650 mg, codeine 60 mg, pentazocine 50 mg or oxycodone 10 mg plus paracetamol 650 mg). All doses of flupirtine produced analgesia after a single dose. Pharmacokinetic evaluations have shown linear kinetics for flupirtine and a 100 mg t.i.d. dosage schedule produces average steady-state blood levels equivalent to the peak response for a single 200 mg dose. Adverse experiences occurring in flupirtine clinical studies have been minimal in incidence, nature and degree, with drowsiness being the most frequently reported reaction (approximately 10%).

Azelastine, a novel antiallergic medication, was compared with chlorpheniramine maleate and placebo for efficacy and safety in the treatment of spring allergic rhinitis in a multicenter, double-blind, multiple-dose, parallel-groups study. One hundred fifty-five subjects participated. Subjects ranged in age from 18 to 60 years of age and had at least a 2-year history of spring allergic rhinitis, confirmed by positive skin test to spring aeroallergens. Medications were given four times daily; the azelastine groups received 0.5, 1.0, or 2.0 mg in the morning and evening with placebo in the early and late afternoon; the chlorpheniramine group received 4.0 mg four times daily. Daily subject symptom cards were completed during a screening period to assess pretreatment symptoms and during a 4-week treatment period while subjects received study medications. Individual symptoms, total symptoms, and major symptoms were compared to determine efficacy of medication. Elicited, volunteered, and observed adverse experiences were recorded for each subject and compared among groups. Vital signs, body weights, serum chemistry values, complete blood cell counts, urine studies, and electrocardiograms were obtained for each subject and compared among groups. Symptoms relief in the group receiving the highest concentration of azelastine (2.0 mg twice daily) was statistically greater than in the placebo group during all weeks of the study. Lower doses of azelastine were statistically more effective than placebo only during portions of the first 3 weeks of the study. In contrast, although the chlorpheniramine group did have fewer symptoms than the placebo group during the study, the difference never reached statistical significance during any week of the study. There were no serious side effects in any of the treatment groups. Drowsiness and altered taste perception were increased significantly over placebo only in the high-dose azelastine group. Azelastine appears to be a safe, efficacious medication for seasonal allergic rhinitis.

A series of 25 aryloxypropanolamines containing the 3-indolyl-tert-butyl [i.e., 1,1-dimethyl-2-(1H-indol-3-yl)ethyl] or substituted 3-indolyl-tert-butyl moiety as the N substituent is reported. These compounds have been tested for antihypertensive activity in spontaneously hypertensive rats (SHR), beta-adrenergic receptor antagonist action in conscious normotensive rats, vasodilating activity in ganglion-blocked rats with blood pressure maintained by angiotensin II infusion, and for intrinsic sympathomimetic action (ISA) in reserpinized rats. Some of the compounds exhibit antihypertensive activity in combination with beta adrenergic receptor antagonist and vasodilating action. The structure--activity relationships in these tests are discussed.

Azelastine hydrochloride, chemically known as 1(2H)-phthalazinone, 4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepine-4-yl)-, monohydrochloride, is a novel, orally effective, long-acting, antiallergic/antiasthmatic agent. The ability of azelastine and selected antiallergic drugs to inhibit SRS-A (leukotriene)-mediated acute lung anaphylaxis in guinea pigs (Konzett-Rossler method) was investigated. Azelastine and ketotifen were administered p.o. 2 and 24 h before antigen challenge; disodium cromoglycate (DSCG) was administered i.v. immediately before antigen challenge. The oral dose of azelastine required to inhibit leukotriene-mediated allergic bronchospasm by 50% (ID50: mg/kg) was 0.063 at 2 h and 0.120 at 24 h. Ketotifen at a dose of 0.05 to 10 mg/kg at 2 and 24 h, p.o., as well as DSCG at a dosage of 0.3 to 10 mg/kg at 0 min, i.v., produced weak, inconsistent and nondose-related antianaphylactic effects. Azelastine is an orally effective and long-acting inhibitor of in vivo synthesis and/or release of leukotrienes.

Azelastine is a chemically novel medication that has been demonstrated to be clinically effective for asthma and seasonal allergic rhinitis. In a 10-week, multicenter, double-blind, placebo-controlled, crossover study, the efficacy and safety of azelastine, 1 mg and 2 mg twice daily, were evaluated in 192 patients with symptoms of perennial allergic rhinitis. Patients maintained daily symptom and adverse-experience diaries and were evaluated every 2 weeks by the investigators. Pseudoephedrine, 30 mg, was provided as backup medication. Amelioration of most individual symptoms and a decrease in the total symptom scores were observed with both dosages of azelastine; greater improvement with 2 mg twice daily than with 1 mg twice daily, was observed. Nasal congestion, as a symptom and as reflected by rhinomanometric assessment, was the least improved parameter. Backup decongestant medication decreased during treatment with azelastine and increased during the placebo regimen. There were no major adverse effects.

Antihypertensive activity of 2-amino-4-(3,4-dichlorophenyl)-2-imidazoline hydrobromide (MJ 10459-2) was assessed in conscious, spontaneously hypertensive and stress-induced hypertensive rats via indirect determination of systolic blood pressure. Subcutaneous administration of 1-4 mg/kg resulted in lowering of blood pressure that was dose related. No reductions in the content of norepinephrine, dopamine, serotonin or 5-hydroxyindoleacetic acid were noted in the cerebrum, cerebellum, midbrain or medulla/pons area of brain after 1 and 4 mg/kg of MJ 10459-2. Cardiac tissue norepinephrine was reduced to 4-6% of control values after subcutaneous doses of 0.2-20 mg/kg of MJ 10459-2 in hypertensive and normotensive rats. These data suggest that at least part of the blood pressure lowering effects of MJ 10459-2 may involve reduction of peripheral noradrenergic stores.

In the aortas and mesenteric arteries from spontaneous hypertensive rats and in the aortas from stress- and desoxycorticosterone-acetate-hypertensive rats, the intracellular cGMP: cAMP ratios were significantly elevated when compared to the ratios in the aortas of the respective controls. Decreases in the intracellular cAMP or cGMP levels were consistently associated with increased activity of the cyclic-nucleotide-specific low K(m) phosphodiesterase (3':5'-cAMP 5' nucleotidohydrolase, EC 3.1.4.17). Increases in intracellular cGMP levels were associated with elevated guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity. Furthermore, adenylyl cyclase [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] activity was less sensitive to stimulation by the beta-adrenergic stimulant isoproterenol in both the aortas and the hearts of the hypertensive animals. These changes could provide the biochemical basis for the (a) increased vascular smooth muscle tone and peripheral resistance observed in these animals, (b) increased reactivity to norepinephrine, and (c) decreased ability of aortas from hypertensive rats to relax. The presence of these same effects in different etiologic types of hypertension indicates that this aberration in cyclic nucleotide metabolism may represent a common metabolic defect basic to the hypertensive syndrome irrespective of etiology.

The ability of azelastine and selected antiallergic drugs to inhibit compound 48/80-induced and PS-potentiated, Con A-induced histamine release from RPMC was investigated. Azelastine, ketotifen, theophylline, and DSCG added simultaneously with the secretagogues or preincubated with the RPMC for 10 min before the addition of secretagogues produced concentration-dependent inhibition of histamine release. In general, the relative order of potency at calculated IC50 level was as follows: azelastine greater than ketotifen greater than theophylline greater than DSCG. The preincubation of RPMC with azelastine for 10 min exerted 3.5 times greater inhibition of Con A plus PS-stimulated histamine release but did not influence the inhibitory activity on compound 48/80-induced release. The duration of preincubation did not influence the inhibitory effects of ketotifen with either secretagogue. Theophylline and DSCG exerted significantly greater inhibition when they were added simultaneously with Con A plus PS. The inhibitory activity of DSCG was also significantly improved upon simultaneous addition with compound 48/80. These data demonstrated that azelastine is the most potent inhibitor of nonallergic histamine release from RPMC among the four antiallergic drugs examined.

Azelastine is capable of interfering with a wide variety of mediators of airway hyperreactivity and provides significant protection and bronchodilation in allergic hay fever and allergic asthma, respectively. Clinical studies have shown that azelastine produces clinically significant bronchodilation of long duration in moderate to severe reversible lower airway disease. In addition, azelastine has been shown to have an effect on the upper airways by effective symptom relief in patients with seasonal allergic rhinitis; furthermore, azelastine affords protection against exercise and allergen provocation.

Bradykinin-induced bronchoconstriction is due, in part, to release of TXA2 and prostaglandins. Intravenous administration of meseclazone and other nonsteroidal anti-inflammatory drugs caused a dose-dependent inhibition of bronchoconstriction resulting in the following order of descending potency: isoproterenol congruent to indomethacin greater than fenoprofen greater than tolmetin greater than aspirin greater than naproxen congruent to ibuprofen greater than phenylbutazone greater than diflunisal greater than meseclazone greater than 5-CSA. This order of potency does not correlate with that obtained with these compounds for in vitro relaxation of tracheal smooth muscle, an effect which may be related to inhibition of prostaglandin synthesis.